The present invention is directed to a process for converting amorphous and/or meta-stable crystalline regions of particles into a crystalline state, the resulting particles being useful e.g. for oral or nasal inhalation.
The increasing production and use of fine powders in the pharmaceutical industry has high-lighted the need for reliable methods for assessing their physicochemical and technical handling. Particles obtained by spray drying, freeze drying, rapid solvent quenching or from controlled precipitation will often be in an amorphous state and/or in a meta-stable crystalline form. For crystalline substances, a diminution operation, e.g. micronization, will give particles with amorphous regions.
The usefulness of amorphous and/or meta-stable crystalline particles is limited due to their thermodynamic instability. For example, such particles tend to fuse in the presence of moisture, thereby forming hard agglomerates which are difficult to break up. Furthermore, amorphous and/or meta-stable crystalline particles exhibit larger batch-to-batch variations as regards bulk density than do well-defined crystalline particles. This may cause problems e.g. in inhalers for treating respiratory disorders, due to lower dosing accuracy.
It is therefore desirable to convert the amorphous or meta-stable crystalline particles into a crystalline, and therefore, more stable state.
Methods to convert the amorphous or meta-stable crystalline particles into crystalline particles are known. Examples are disclosed in U.S. Pat. No. 5,709,884 and U.S. Pat. No. 5,562,923 both to Astra AB of Sweden.
The known methods to convert amorphous or meta-stable crystalline particles into crystal-line particles are, however, often time consuming requiring substantial space. Therefore, there is a need for a more efficient technique for producing crystalline particles with a high shelf life.
The object of the present invention is to provide a process for crystallization of amorphous and/or meta-stable crystalline regions of particles e.g. obtained in a preceding micronization stage, comprising treating the particles under supercritical or subcritical conditions with an anti-solvent and a solvent.
According to a preferred embodiment of the invention, the anti-solvent and solvent are carbon dioxide and water, respectively.
According to another preferred embodiment, the relative solvent saturation of the anti-solvent lies in the range of from 15% up to 50% of total solvent saturation at the prevailing pressure and temperature.